US3254088A - Morphine derivative - Google Patents

Morphine derivative Download PDF

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Publication number
US3254088A
US3254088A US95506A US9550661A US3254088A US 3254088 A US3254088 A US 3254088A US 95506 A US95506 A US 95506A US 9550661 A US9550661 A US 9550661A US 3254088 A US3254088 A US 3254088A
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United States
Prior art keywords
hydroxydihydro
morphinone
allyl
morphine
acid
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US95506A
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Lewenstein Mozes Juda
Gardens Kew
Fishman Jack
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LEWENSTEIN
EIDP Inc
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LEWENSTEIN
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Priority to US95506A priority Critical patent/US3254088A/en
Priority to GB46475/61A priority patent/GB955493A/en
Priority to DEL41404A priority patent/DE1183508B/en
Priority to US339580A priority patent/US3493657A/en
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Publication of US3254088A publication Critical patent/US3254088A/en
Assigned to E.I. DU PONT DE NEMOURS AND COMPANY reassignment E.I. DU PONT DE NEMOURS AND COMPANY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ENDO LABORATORIES, INC., A CORP. OF DEL.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • Example 1 10 grams of 14-hydroxydihydromorphinone was converted into its diacetate by warming it on the steam bath with 80 ccm. of acetic anhydride for about 2 hours. The acetic anhydride was removed on the water bath under a vacuum of about 30- mm. absolute pressure. The melting point of the residue was 220 C. The residue was taken up in 100 ccm. of chloroform. An equal amount by weight of cyanogen bromide was added and the mixture was refluxed at about 60 C. for about 5 hours. After refluxing, the mixture was washed with 100 cc. of a 5% aqueous hydrochloric acid solution, dried over sodium sulfate and the chloroform removed by evaporation under a vacuum of about 30 mm. The residue had a melting point of 240 C.
  • the residue was then heated at about 90 C. for 16 hours on a steam bath with 300 ccm. of 20% aqueous hydrochloric acid solution, and treated with a small amount, e.g. 1 gram of charcoal.
  • the hydrochloric acid was then removed under a vacuum of 15 mm., the residue dissolved in 30 ccm. of water and precipitated by the addition of 2.4 ccm. of concentrated aqueous ammonia.
  • the precipitate was filtered off and dried. It consists of 14-hydroxydihydro-nor-morphinone. It has no melting point and is soluble in ethanol.
  • the l4-hydroxydihydro-nor-morph.inone was suspended in 200 ccm. of pure ethyl alcohol, half its weight of sodium bicarbonate and half its weight of allyl bromide added and the resulting mixture was refluxed at about 75 C. for 48 hours.
  • the solution was cooled e.g. to C. and filtered and the alcohol removed under a vacuum of 30 mm.
  • the residue was dissolved in chloroform and filtered.
  • the chloroform was removed under a vacuum of 30 mm. and the residue was crystallized from ethylacetate.
  • the crystallized product N-allyl-14- hydroxydihydro-nor-morphinone, has a melting point of 184 C., is soluble in chloroform and insoluble in pe- The yield amounts to 20% based on the weight of the reacted 14-hydroxydihydromorphinone.
  • N-allyl-hydroxydihydro-nor-morphinone contains C 69.72% and H 6.43%, N 4.28%. Found: C 69.54%, H 6.87%, N 4.43%.
  • Example 3 One gram of N-allyl-14-hydroxydihydro-nor-morphinone was dissolved in 50 cc. of ethanol. An equivalent of tartaric acid was added and the solution was warmed. Evaporation of solvent yielded the bitartrate salt which could be crystallized from dilute ethanol.
  • Salts of 14-hydroxydihydro-nor-morphinone can be prepared substantially in the same manner as described in the above Examples 2 and 3.
  • the compounds embodying this invention are of low toxicity so that they can be used without the danger of toxic effects when administered to human subjects.
  • the compounds of the present invention can be administered prior to or after administration of the analgesics, or in mixture with the analgesics, preferably by intravenous, subcutaneous, or intramuscular injection.
  • N-al'lyl-14-hydroxydihydro-nor-morphinone and its salts are antagonists of unexpectedly high potency against the respiratory depressive action of potent analgesics.
  • the new compounds are about 10 times more potent in antagonistic action than N-allylnor-morphine. It has been found that in order to counteract the depression produced by morphine, the action of 0.1 mg. of the compound of this invention per 10 mg. morphine, was suflicient. Furthermore of great importance is the fact that the compounds of this invention act much faster than N-allyl-nor-morphine.
  • narcotic drugs such as morphine
  • the antagonists of this invention are considerably better tolerated by human subjects.
  • therapeutically applicable salt is used herein to denote salts in which the acid ingredient of the salt is free of toxicity or other therapeutically harmful or undesired effects.
  • the process described above is not limited to the specific conditions, steps, amounts and other details specifically described in the above examples and can be carried out with various modifications.
  • the acetic anhydride in acetylating the starting material, can be used in any excess which is conventional in acetylating reactions of this type.
  • the residue obtained by the removal of acetic anhydride can be dissolved in 20 to ccm. chloroform or more.
  • the cyanogenbromide is preferably used in an amount of at least 3 mols for each mol of 14-hydroxydihydromorphinone, but the use of more cyanogenbromide is not necessary or useful.
  • the reaction with cyanogenbromide by refluxing may take place, depending on the solvent, in the range of 30 to 200 C.
  • the residue obtained by washing and drying the refluxed liquid and removing the chloroform is then heated for 4 to 20 hours with 100 to 400 ccm. of 20% aqueous HCl at 60-*100 C.
  • the solution obtained by the removal of the aqueous HCl, and dissolution of the residue in water is precipitated by the addition of 1 to 20 ccm of concentrated aqueous ammonia.
  • the filtered ofi and dried precipitate is suspended in 50 to 250 com. of an alcohol, e.g. ethyl alcohol and is reacted after the addition of sodium bicarbonate and allyl bromide by refluxing at 50150 C. for 24 to 72 hours.

Description

'troleum ether.
United States Patent 3,254,088 MORPHINE DERIVATIVE Mozes Juda Lewenstein, 80-49 Park Lane, Kew Gardens, Long Island, N.Y., and Jack Fishman, Rego Park, N.Y.; said Fishman assignor to said Lewenstein No Drawing. Filed Mar. 14, 1961, Ser. No. 95,506 4 Claims. (Cl. 260-285) This invention relates to new morphine derivatives and has particular relation to N-allyl-14-hydroxydihydronor-morphinone and its salts and to a process for preparing the same. The invention also relates to 14-hydroxydihydro-nor-morphinone and its salts.
It has been known that certain morphine derivatives are antagonists against the respiratory depressive action of opium alkaloids, their derivatives and synthetic analgesics. Several such antidotes have been made in the past, such as N-allylnormorphine and levallorphan. We have now found that compounds of this invention, i.e. N- allyl-14-hydroxydihydro-nor-morphinone and its therapeutically applicable salts are more potent antagonists to the respiratory depressive effects of potent analgesics than the antagonists hitherto known. The 14-hydroxydihydro-nor-morphinone has been found to be a potent and effective analgesic.
The following examples'descn'be some specific embodiments of and best modes for preparing the compounds of the invention, to which the invention is not limited.
Example 1 10 grams of 14-hydroxydihydromorphinone was converted into its diacetate by warming it on the steam bath with 80 ccm. of acetic anhydride for about 2 hours. The acetic anhydride was removed on the water bath under a vacuum of about 30- mm. absolute pressure. The melting point of the residue was 220 C. The residue was taken up in 100 ccm. of chloroform. An equal amount by weight of cyanogen bromide was added and the mixture was refluxed at about 60 C. for about 5 hours. After refluxing, the mixture was washed with 100 cc. of a 5% aqueous hydrochloric acid solution, dried over sodium sulfate and the chloroform removed by evaporation under a vacuum of about 30 mm. The residue had a melting point of 240 C.
The residue was then heated at about 90 C. for 16 hours on a steam bath with 300 ccm. of 20% aqueous hydrochloric acid solution, and treated with a small amount, e.g. 1 gram of charcoal. The hydrochloric acid was then removed under a vacuum of 15 mm., the residue dissolved in 30 ccm. of water and precipitated by the addition of 2.4 ccm. of concentrated aqueous ammonia. The precipitate was filtered off and dried. It consists of 14-hydroxydihydro-nor-morphinone. It has no melting point and is soluble in ethanol.
The l4-hydroxydihydro-nor-morph.inone was suspended in 200 ccm. of pure ethyl alcohol, half its weight of sodium bicarbonate and half its weight of allyl bromide added and the resulting mixture was refluxed at about 75 C. for 48 hours. The solution was cooled e.g. to C. and filtered and the alcohol removed under a vacuum of 30 mm. The residue was dissolved in chloroform and filtered. The chloroform was removed under a vacuum of 30 mm. and the residue was crystallized from ethylacetate. The crystallized product, N-allyl-14- hydroxydihydro-nor-morphinone, has a melting point of 184 C., is soluble in chloroform and insoluble in pe- The yield amounts to 20% based on the weight of the reacted 14-hydroxydihydromorphinone.
Calculated for the free base, the N-allyl-hydroxydihydro-nor-morphinone contains C 69.72% and H 6.43%, N 4.28%. Found: C 69.54%, H 6.87%, N 4.43%.
Patented May 31, 1966 Example 2 One gram of N-allyl-14-hydroxydihydr0-nor-morphinone was dissolved in 50 cc. of ethanol. An equivalent of 6 N hydrochloric acid was added. Addition of ether precipitated the hydrochloric salt which could be crystallized from ethanol-ether.
Example 3 One gram of N-allyl-14-hydroxydihydro-nor-morphinone was dissolved in 50 cc. of ethanol. An equivalent of tartaric acid was added and the solution was warmed. Evaporation of solvent yielded the bitartrate salt which could be crystallized from dilute ethanol.
Salts of 14-hydroxydihydro-nor-morphinone can be prepared substantially in the same manner as described in the above Examples 2 and 3.
As further examples of acids which can be used for preparing salts of the new'bases, the following are mentioned: sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, oxalic acid, maleic acid, succinic acid, benzoic acid, and lactic acid.
The compounds embodying this invention are of low toxicity so that they can be used without the danger of toxic effects when administered to human subjects.
In obtaining the desired antagonizing effects, the compounds of the present invention can be administered prior to or after administration of the analgesics, or in mixture with the analgesics, preferably by intravenous, subcutaneous, or intramuscular injection.
The N-al'lyl-14-hydroxydihydro-nor-morphinone and its salts are antagonists of unexpectedly high potency against the respiratory depressive action of potent analgesics. For example, the new compounds are about 10 times more potent in antagonistic action than N-allylnor-morphine. It has been found that in order to counteract the depression produced by morphine, the action of 0.1 mg. of the compound of this invention per 10 mg. morphine, was suflicient. Furthermore of great importance is the fact that the compounds of this invention act much faster than N-allyl-nor-morphine. In cases of over-doses of narcotic drugs, such as morphine, it often is a matter of the greatest urgency to use a fast acting antagonist and the difference in the onset of action between N-allyl-nor-morphine and the present new compound may make a difference between life and death. In addition the antagonists of this invention are considerably better tolerated by human subjects.
The term therapeutically applicable salt is used herein to denote salts in which the acid ingredient of the salt is free of toxicity or other therapeutically harmful or undesired effects.
It will be understood that the process described above is not limited to the specific conditions, steps, amounts and other details specifically described in the above examples and can be carried out with various modifications. For example, in acetylating the starting material, the acetic anhydride can be used in any excess which is conventional in acetylating reactions of this type. The residue obtained by the removal of acetic anhydride can be dissolved in 20 to ccm. chloroform or more. The cyanogenbromide is preferably used in an amount of at least 3 mols for each mol of 14-hydroxydihydromorphinone, but the use of more cyanogenbromide is not necessary or useful. The reaction with cyanogenbromide by refluxing may take place, depending on the solvent, in the range of 30 to 200 C. The residue obtained by washing and drying the refluxed liquid and removing the chloroform is then heated for 4 to 20 hours with 100 to 400 ccm. of 20% aqueous HCl at 60-*100 C. The solution obtained by the removal of the aqueous HCl, and dissolution of the residue in water is precipitated by the addition of 1 to 20 ccm of concentrated aqueous ammonia. The filtered ofi and dried precipitate is suspended in 50 to 250 com. of an alcohol, e.g. ethyl alcohol and is reacted after the addition of sodium bicarbonate and allyl bromide by refluxing at 50150 C. for 24 to 72 hours. These and similar modifications can be made without departing from the scope of the invention as defined in the appended claims.
What is claimed is:
1. A compound selected from the group consisting of N-ally-l-14-hydroxydihydro-nor-morphinone and its therapeutically applicable salts. I
2. The compound N-allyl-14-hydroxydihydro-normorphinone.
3. A compound consisting of a therapeutically applicable salt of N-allyl-14-hydroxydihydro-nor-morphinone.
4. A compound consisting of the hydrochloric salt of N-allyl-14-hydroxydihydro-nor-morphinone.-
. References Cited by the Examiner UNITED STATES PATENTS OTHER REFERENCES I Beilstein: Handbuch der Organischen Chemie, vol 27, Second Work, pages 359-360 (1955).
Winter et al.: Arch. Internat., Pharmacodynamie, vol. 110, pages 186-202 (1957).
20 HENRY R. JILES, Acting Primary Examiner.
IRVING MARCUS, WALTER A. MODANCE,
' Examiners.
E. F. BERG, DON M. KERR, Assistant Examiners.

Claims (1)

  1. 2. THE COMPOUND N-ALLYL-14-HYDROXYDIHYDRO-NORMORPHINONE.
US95506A 1961-03-14 1961-03-14 Morphine derivative Expired - Lifetime US3254088A (en)

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US95506A US3254088A (en) 1961-03-14 1961-03-14 Morphine derivative
GB46475/61A GB955493A (en) 1961-03-14 1961-12-28 Improvements in or relating to morphine derivatives
DEL41404A DE1183508B (en) 1961-03-14 1962-03-07 Process for the preparation of N-allyl-14-hydroxydihydronormorphinone and its salts
US339580A US3493657A (en) 1961-03-14 1964-01-23 Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine

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Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3476757A (en) * 1966-04-18 1969-11-04 Syntex Corp Tetrahydropyranyl and tetrahydrofuranyl ethers of benzomorphans and morphanans
US3676557A (en) * 1971-03-02 1972-07-11 Endo Lab Long-acting narcotic antagonist formulations
US3966940A (en) * 1973-11-09 1976-06-29 Bristol-Myers Company Analgetic compositions
US4141897A (en) * 1976-12-20 1979-02-27 Research Corporation N-dealkylation of N-alkyl-14-hydroxymorphinans and derivatives thereof
US4181726A (en) * 1978-11-16 1980-01-01 Bernstein Joel E Method of alleviating pruritis
US4267182A (en) * 1979-01-16 1981-05-12 The United States Of America As Represented By The Secretary Of The Army Narcotic antagonists in the therapy of shock
WO1983003197A1 (en) 1982-03-16 1983-09-29 Univ Rockefeller Method for controlling gastrointestinal dysmotility
US4457933A (en) * 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
US4466968A (en) * 1980-11-24 1984-08-21 Dermall, Ltd. Method for prophylaxis or treatment of emesis and nausea
US4668685A (en) * 1984-07-05 1987-05-26 E.I. Du Pont De Nemours And Company Substituted benzoate ester prodrug derivatives of 3-hydroxymorphinans, which are analgesics or narcotic antagonists
US4775759A (en) * 1984-11-27 1988-10-04 The United States Of America As Represented By The Department Of Health And Human Services Synthesis and utilization of 17-methyl and 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy 6β-fluoromorphinans (foxy and cyclofoxy) as (18F)-labeled opioid ligands for position emission transaxial tomography (PETT)
US4987136A (en) * 1982-03-16 1991-01-22 The Rockefeller University Method for controlling gastrointestinal dysmotility
US5336483A (en) * 1991-06-14 1994-08-09 The United States Of America As Represented By The Department Of Health And Human Services Radiolabeled n-substituted-6-iodo-3,14-dihydroxy-4, 5α-epoxymorphinans, intermediates for producing the same, and a process for the preparation and methods of detecting opioid receptors
WO1996000573A1 (en) * 1994-06-30 1996-01-11 Bio-Logic Research And Development Corporation Compositions for enhancing immune function
US6455537B1 (en) 1999-08-25 2002-09-24 Barrett R. Cooper Methods for treating opiate intolerance
US6713488B2 (en) 2000-03-15 2004-03-30 Sadee Wolfgang Neutral antagonists and use thereof in treating drug abuse
WO2005028483A1 (en) 2003-09-22 2005-03-31 Glaxosmithkline Australia Pty Ltd Process for the synthesis of morphinane compounds and intermediates thereof
US20060003007A1 (en) * 2004-07-01 2006-01-05 Isa Odidi Controlled extended drug release technology
US20070015138A1 (en) * 2005-07-08 2007-01-18 Braincells, Inc. Methods for identifying agents and conditions that modulate neurogenesis
US20070166370A1 (en) * 2003-06-26 2007-07-19 Isa Odidi Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
WO2007124114A2 (en) 2006-04-21 2007-11-01 Nektar Therapeutics Al, Corporation Stereoselective reduction of a morphinone
US20080045716A1 (en) * 2003-09-22 2008-02-21 Craig Smith Process for the synthesis of morphinane compounds and intermediates thereof
US20090220613A1 (en) * 2006-04-03 2009-09-03 Isa Odidi Controlled release delivery device comprising an organosol coat
US20090232887A1 (en) * 2006-05-12 2009-09-17 Isa Odidi Pharmaceutical composition having reduced abuse potential
WO2010009451A2 (en) 2008-07-17 2010-01-21 Merial Limited Long-acting injectable analgesic formulations for animals
US20100048602A1 (en) * 2007-03-12 2010-02-25 Nektar Therapeutics Oligomer-Opioid Agonist Conjugates
CN102174049A (en) * 2011-03-11 2011-09-07 山东新华制药股份有限公司 Process for salifying naloxone hydrochloride
US20110237614A1 (en) * 2008-09-16 2011-09-29 Nektar Therapeutics Pegylated Opioids with Low Potential for Abuse
WO2011154826A1 (en) 2010-06-11 2011-12-15 Rhodes Technologies Process for n-dealkylation of tertiary amines
WO2011154827A2 (en) 2010-06-11 2011-12-15 Rhodes Technologies Transition metal-catalyzed processes for the preparation of n-allyl compounds and use thereof
WO2014170704A1 (en) 2013-04-15 2014-10-23 Szegedi Tudományegyetem Deuterated morphine derivatives
EP3042908A1 (en) 2011-05-02 2016-07-13 Brock University Intermediates in the preparation of morphine analogs
US9522119B2 (en) 2014-07-15 2016-12-20 Isa Odidi Compositions and methods for reducing overdose
EP3252055A1 (en) 2016-05-31 2017-12-06 Alcaliber Investigacion Desarrollo e Innovacion, S.L. Process for obtaining 3,14-diacetyloxymorphone from oripavine
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
US10512644B2 (en) 2007-03-12 2019-12-24 Inheris Pharmaceuticals, Inc. Oligomer-opioid agonist conjugates
US10624858B2 (en) 2004-08-23 2020-04-21 Intellipharmaceutics Corp Controlled release composition using transition coating, and method of preparing same
US11247999B1 (en) 2021-07-02 2022-02-15 Joseph DeGraw Facile conversion of morphine to normorphine
EP4174072A2 (en) 2013-08-02 2023-05-03 Macfarlan Smith Limited Process for the preparation of morphinan-6-one compounds

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GB717008A (en) * 1951-05-29 1954-10-20 Mozes Juda Lewenstein Morphine derivative
US2741613A (en) * 1952-11-22 1956-04-10 Merck & Co Inc N-substituted dihydronormorphinone compounds
US2890221A (en) * 1957-07-24 1959-06-09 Rapoport Henry Method for preparing normorphine
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GB717008A (en) * 1951-05-29 1954-10-20 Mozes Juda Lewenstein Morphine derivative
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US2891954A (en) * 1953-07-30 1959-06-23 Merck & Co Inc Process for preparing n-allylnormorphine
US2890221A (en) * 1957-07-24 1959-06-09 Rapoport Henry Method for preparing normorphine

Cited By (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3476757A (en) * 1966-04-18 1969-11-04 Syntex Corp Tetrahydropyranyl and tetrahydrofuranyl ethers of benzomorphans and morphanans
US3676557A (en) * 1971-03-02 1972-07-11 Endo Lab Long-acting narcotic antagonist formulations
US3966940A (en) * 1973-11-09 1976-06-29 Bristol-Myers Company Analgetic compositions
US4141897A (en) * 1976-12-20 1979-02-27 Research Corporation N-dealkylation of N-alkyl-14-hydroxymorphinans and derivatives thereof
US4181726A (en) * 1978-11-16 1980-01-01 Bernstein Joel E Method of alleviating pruritis
US4267182A (en) * 1979-01-16 1981-05-12 The United States Of America As Represented By The Secretary Of The Army Narcotic antagonists in the therapy of shock
US4457933A (en) * 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
US4466968A (en) * 1980-11-24 1984-08-21 Dermall, Ltd. Method for prophylaxis or treatment of emesis and nausea
WO1983003197A1 (en) 1982-03-16 1983-09-29 Univ Rockefeller Method for controlling gastrointestinal dysmotility
US4987136A (en) * 1982-03-16 1991-01-22 The Rockefeller University Method for controlling gastrointestinal dysmotility
US4668685A (en) * 1984-07-05 1987-05-26 E.I. Du Pont De Nemours And Company Substituted benzoate ester prodrug derivatives of 3-hydroxymorphinans, which are analgesics or narcotic antagonists
US4775759A (en) * 1984-11-27 1988-10-04 The United States Of America As Represented By The Department Of Health And Human Services Synthesis and utilization of 17-methyl and 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy 6β-fluoromorphinans (foxy and cyclofoxy) as (18F)-labeled opioid ligands for position emission transaxial tomography (PETT)
US5336483A (en) * 1991-06-14 1994-08-09 The United States Of America As Represented By The Department Of Health And Human Services Radiolabeled n-substituted-6-iodo-3,14-dihydroxy-4, 5α-epoxymorphinans, intermediates for producing the same, and a process for the preparation and methods of detecting opioid receptors
US5888980A (en) * 1994-06-30 1999-03-30 Bio-Logic Research And Development Corporation Compositions for enhancing immune function
WO1996000573A1 (en) * 1994-06-30 1996-01-11 Bio-Logic Research And Development Corporation Compositions for enhancing immune function
US6455537B1 (en) 1999-08-25 2002-09-24 Barrett R. Cooper Methods for treating opiate intolerance
US20030018043A1 (en) * 1999-08-25 2003-01-23 Cooper Barrett R. Compositions and methods for treating opiate intolerance
US6713488B2 (en) 2000-03-15 2004-03-30 Sadee Wolfgang Neutral antagonists and use thereof in treating drug abuse
US8802139B2 (en) 2003-06-26 2014-08-12 Intellipharmaceutics Corp. Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US9636306B2 (en) 2003-06-26 2017-05-02 Intellipharmaceutics Corp. Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US8603520B2 (en) 2003-06-26 2013-12-10 Intellipharmaceutics Corp. Oral multi-functional pharmaceutical capsule preparations of proton pump inhibitors
US20070166370A1 (en) * 2003-06-26 2007-07-19 Isa Odidi Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
WO2005028483A1 (en) 2003-09-22 2005-03-31 Glaxosmithkline Australia Pty Ltd Process for the synthesis of morphinane compounds and intermediates thereof
US20080045716A1 (en) * 2003-09-22 2008-02-21 Craig Smith Process for the synthesis of morphinane compounds and intermediates thereof
US8106201B2 (en) 2003-09-22 2012-01-31 Johnson Matthey Public Limited Company Process for the synthesis of morphinane compounds and intermediates thereof
US7875718B2 (en) 2003-09-22 2011-01-25 Johnson Matthey Public Limited Company Process for the synthesis of morphinane compounds and intermediates thereof
US20110098474A1 (en) * 2003-09-22 2011-04-28 Johnson Matthey Public Limited Company Process for the synthesis of morphinane compounds and intermediates thereof
US20060003007A1 (en) * 2004-07-01 2006-01-05 Isa Odidi Controlled extended drug release technology
US8394409B2 (en) 2004-07-01 2013-03-12 Intellipharmaceutics Corp. Controlled extended drug release technology
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